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Is it important to rank the individual drugs within a class?
At the clinical level it may seem unimportant to rank a group of drugs that essentially have the same clinical profile. However, with the triptans there has been intense pressure from the individual manufacturers to attempt to place their triptan in an advantageous position relative to the others. Many claims have been made that may not be justified by the clinical significance of the evidence available. In such a confused area, it is worth evaluating the evidence that compares the triptans in an objective way, to try to provide guidance for the physician.4.76
How can we understand the evidence used to compare the
triptans?
The evidence from clinical studies can be ranked in order of quality, as follows:
■
Large, randomised, controlled clinical trials that compare two or more drugs■
Meta-analyses of clinical data■
Smaller randomised studies, open studies and case series■
Post hoc data derived from selected clinical studies■
Consensus agreements between groups of physicians.The quality of the clinical data comparing the triptans is not optimal. Relatively few large, randomised, controlled trials have compared the clinical profiles of the different triptans and most of these compare the newer oral drugs with the gold standard of oral sumatriptan. One meta- analysis has recently been published that compares the oral triptans. There have also been many post hoc analyses of clinical data which do not provide
conclusive evidence of superiority but only suggest future avenues for research. Data analysed in these post hoc analyses include:
■
The active response rate (ARR): the proportion of patients reporting headache relief with the triptan■
Placebo response rate (PRR): the proportion of patients reporting headache relief with placebo■
The therapeutic gain (TG): the ARR minus the PRR■
The number needed to treat (NNT): the number of patients it is necessary to treat to achieve one patient with a successful response, adjusted for placebo; this is the reciprocal of the TG.However, it should be recognised that results from clinical trials do not necessarily equate with those observed in everyday clinical practice. The patients recruited into clinical trials are often not representative of the population with the illness. In the clinic, efficacy rates may be different from those reported in clinical trials and new side effects may emerge following long-term use. The true clinical profile of a drug only reveals itself after extensive use in the clinic.
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How do the triptans rank in terms of clinical profile?
The clinical profiles of the different triptans are summarised in Table 4.2. It needs to be recognised that all the triptans are effective and well tolerated acute treatments for moderate to severe migraine. The most effective triptan is subcutaneous sumatriptan 6 mg, which has the greatest 2-hour efficacy and fastest onset of action. Following this, the nasal spray triptans, sumatriptan 20 mg and zolmitriptan 5 mg, have faster onsets of action and possibly slightly greater efficacy than any of the oral formulations.
There seem to be only minor differences in the clinical profile of the oral triptans. The randomised, controlled comparator studies that have been conducted tend to show only small differences between the separate drugs based on secondary endpoints. The meta-analysis of the oral triptans concluded that all available oral triptans are effective and well tolerated acute treatments for migraine but suggested that rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provided the highest likelihood of consistent success. These conclusions have been reinforced by post hoc analyses of selected clinical data and require further investigation in controlled clinical trials. Interestingly, the clinical profile of the ODT formulations of zolmitriptan and rizatriptan are similar to those of the equivalent conventional tablets.
Patient preference studies provide an alternative means of rating the triptans. In general, they show that individual patients prefer different triptans for their overall effectiveness and speed of effect. However, it is not possible to predict the triptan that the individual patient will prefer.
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Can the oral triptans be differentiated in terms of their clinical
profiles?
On the available evidence, the overall ranking of oral triptans has been graded as follows: rizatriptan 10 mg = eletriptan 80 mg > sumatriptan 100 mg = zolmitriptan 2.5 mg > almotriptan 12.5 mg > naratriptan 2.5 mg. However, this needs to be balanced with a consideration of tolerability: Adverse events are reported in the rank order eletriptan > zolmitriptan > sumatriptan = rizatriptan > almotriptan > naratriptan. The recently published meta-analysis of all randomised, controlled clinical trials of oral triptans came to the same broad conclusions with rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg having the best efficacy profiles.
The overall conclusion that can be made from these studies is that no one oral triptan is substantially superior to another. There is also considerable debate about issues of study design, marketing spin and encapsulation of certain formulations that reduce the clinical utility of the study results. Many headache experts believe that the meta-analysis comparing the triptans is flawed methodologically. Also, the efficacy of a drug as assessed in clinical trials does not necessarily echo its profile in clinical practice. This has been recognised by the FDA, who require the statement ‘Comparisons of drug performance based on results obtained in different clinical trials are never reliable’ on most triptan labels.
Since patients are treated on an individual basis, the more important question is not which triptan is best relative to another but whether the triptan provided to the patient provides the outcome desired by the patient and healthcare provider. An evaluation of each patient as to their clinical needs and desires should drive the choice of triptan. The factors that should be considered by the physician in prescribing specific triptans are explored in more detail later in this book (see Q 5.xx).
ERGOTS
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What are the ergots?
Ergot (Claviceps purpurea) is a fungus known since the Middle Ages, when its contamination of wheat led to epidemics of gangrene called ‘St Anthony’s Fire’. The main causative agent of this is the alkaloid ergotamine. This was isolated in the early part of the 20th century and has been used as an acute treatment for migraine since the 1920s.
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What is the mode of action of the ergots?
The ergots have a complex mechanism of action, involving interactions with several receptors, including alpha-adrenoreceptors, 5-HT and dopamine D2receptors.
The mechanism of action of ergotamine and its derivatives in migraine is through a long-acting and nonspecific vasoconstrictor action via 5-HT1
receptors. This action acts to constrict the cerebral arteries that are dilated during the migraine attack. However, it also acts on cardiac and leg arteries which leads to unwanted side effects.
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What ergot drugs and formulations are available to the
physician?
Ergotamine has been used for many years as an acute treatment for moderate to severe migraine, sometimes in combination with caffeine on its own, or the combination of caffeine, pentobarbital and belladonna alkaloids. It can be taken orally, by subcutaneous or intramuscular injection or rectally.
DHE is a derivative of ergotamine that was designed to reduce the incidence of the typical side effects associated with ergotamine. It was developed more recently and clinical studies have used modern criteria for study design, patient selection and methodology. DHE is available by intravenous, subcutaneous and intramuscular injection and as a nasal spray.
ERGOTAMINE
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What special precautionary measures must be taken with
ergotamine?
Ergotamine is contraindicated for patients with coronary, peripheral or occlusive vascular disease, hypertension, liver or kidney disease, and in women who are pregnant or lactating.
Ergotamine needs to be used with special care in patients with infectious hepatitis, sepsis, anaemia and hyperthyroidism.
Ergotamine cannot be used with triptans, protease inhibitors,
erythromycin, beta-blockers, CNS depressants and alcohol. The dose needs to be reduced if methysergide is being used for migraine prophylaxis.
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How effective are ergotamine-containing products?
Many studies have investigated the clinical profile of ergotamine and its derivatives. However, due to its age these studies often did not use modern dosing strategies and outcome measures. Overall, evidence of ergotamine’s efficacy is inconsistent, with some studies finding no effect over placebo and others finding large differences favouring ergotamine.
The oral administration of ergotamine is not optimal due to its very low bioavailability (< 1%). Overall, oral ergotamine does shows some
superiority over placebo as an acute migraine treatment. However, oral ergotamine was shown to be statistically inferior to oral sumatriptan 100 mg and aspirin plus metoclopramide in controlled clinical studies. Other comparative studies have shown ergotamine to be equivalent to NSAIDs and inferior to isometheptene combinations.
Ergotamine is more bioavailable (1–3%) when given rectally – this is probably the optimal mode of administration for the drug. However, very few studies have been conducted with this formulation. In one double-blind comparator study, ergotamine suppositories (2mg plus 200 mg caffeine) were superior to sumatriptan suppository 25 mg in terms of the proportion of patients reporting headache relief after 2 hours (73% vs 63%). However, more patients preferred sumatriptan (44% vs 36%) due to its better tolerability profile.
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How can ergotamine be recommended as an acute treatment
for migraine?
Ergotamine is no longer recommended as an acute treatment for migraine. Compared to the triptans it has suboptimal efficacy and tolerability, together with the risk of serious illness in long-term use. If it has to be used at all, the rectal route should be chosen and the oral route avoided.
DHE
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How does the pharmacology of DHE compare with that of
ergotamine?
In general, the pharmacology of DHE is similar to that of ergotamine. DHE is available in parenteral formulations and as a nasal spray. In these formulations, DHE has high bioavailability.
Ergotamine has a suboptimal tolerability profile. Nausea and vomiting are commonly reported as adverse events. Abdominal pain, drowsiness, paraesthesia, swollen fingers and leg cramps may also occur after a single dose. Long-term use is associated with habituation, analgesic rebound headaches, chronic daily headache and leg ischaemia. The clinical use of ergotamine has declined dramatically in recent years and in the UK only the oral combination ergotamine/cyclizin/caffeine product Migril is now available.
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What special precautionary measures must be taken with DHE?
DHE is contraindicated in patients with coronary artery disease,uncontrolled hypertension, known sensitivity to ergot alkaloids, and in pregnant and breast-feeding women.
Although DHE is marketed as an acute treatment for migraine in the USA and many European countries, it is not currently available in the UK.
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How effective is DHE?
Clinical trials have shown that DHE is an effective treatment for moderate to severe migraine. One large, double-blind, controlled clinical study showed that nasal spay DHE 2 mg was significantly superior to placebo as an acute treatment for migraine. At 2 hours after treatment, 65% of patients receiving DHE reported headache relief compared to 23% with placebo (P < 0.01). Also, DHE nasal spray was effective in preventing migraine attacks when given during the prodrome phase.
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How does DHE compare with other migraine therapies?
Large, controlled, comparator clinical trials have shown that subcutaneous and nasal spray DHE was significantly less effective than subcutaneous sumatriptan. Nasal spray DHE was also significantly less effective than nasal spray sumatriptan. However, the long duration of action of DHE resulted in markedly less headache recurrence than was reported with sumatriptan. The headache relief and recurrence rates reported at 2 hours from these studies are shown in Table 4.3.4.89
How can DHE be recommended as an acute treatment for
migraine?
Where they are available, parenteral and nasal spray DHE are effective and reasonably well tolerated acute treatments for migraine. However, the significantly poorer efficacy profile compared to comparable triptan formulations and the potential for safety problems mean that DHE should not be used as a first-line acute treatment. It may be best reserved as a second-line therapy for patients who experience frequent headache recurrences with the triptans.
Although DHE has a better tolerability profile than ergotamine, nausea and vomiting are still frequently reported and co-administration with an antiemetic may be necessary. Other side effects include leg pain and paraesthesia and there are a few reports of angina and ergotism. Additional side effects of transient nasal congestion and throat discomfort are reported with the nasal spray formulation.
ANTIEMETICS
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Are prescription antiemetics effective for migraine?
Antiemetic drugs have been used for the acute treatment of migraine for some time as first-line therapy. However, clinical trials of monotherapy with oral domperidone, prochlorperizine and metoclopramide showed no clinical benefit. However, domperidone and metoclopramide are used together with simple analgesics in combination products which provide effective relief for mild to moderate migraine attacks (see Q 4.xx).
Parenteral prochlorperazine and metoclopramide have demonstrated some efficacy as acute treatments but are not usually used today as monotherapy for migraine. In some countries they are used as rescue therapy, or as adjuncts to other acute treatments.